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Eur J Pharmacol. 2015 Mar 5;750:132-40. doi: 10.1016/j.ejphar.2015.01.037. Epub 2015 Jan 29.

Levosimendan alone and in combination with valsartan prevents stroke in Dahl salt-sensitive rats.

Author information

1
Critical Care Proprietary Products, Orion Pharma, Orionintie 1, P.O. Box 65, FI-02101 Espoo, Finland.
2
Critical Care Proprietary Products, Orion Pharma, Orionintie 1, P.O. Box 65, FI-02101 Espoo, Finland. Electronic address: piero.pollesello@orionpharma.com.
3
A.I.Virtanen Institute for Molecular Sciences, Neulaniementie 2, P.O. Box 1627, FIN-70211 Kuopio, Finland.
4
Tampere University of Technology, Korkeakoulunkatu 10, FI-33720 Tampere, Finland.
5
Cerebricon Ltd., c/o Charles River Laboratories, Microkatu 1, FI-70210 Kuopio, Finland.

Abstract

The effects of levosimendan on cerebrovascular lesions and mortality were investigated in models of primary and secondary stroke. We aimed to determine whether the effects of levosimendan are comparable to and/or cumulative with those of valsartan, and to investigate whether levosimendan-induced vasodilation has a role in its effects on stroke. In a primary stroke Dahl/Rapp rat model, mortality rates were 70% and 5% for vehicle and levosimendan, respectively. Both stroke incidence (85% vs. 10%, P<0.001) and stroke-associated behavioral deficits (7-point neuroscore: 4.59 vs. 5.96, P<0.001) were worse for vehicle compared to levosimendan. In a secondary stroke model in which levosimendan treatment was started after cerebrovascular incidences were already detected, mean survival times were 15 days with vehicle, 20 days with levosimendan (P=0.025, vs. vehicle), 22 days with valsartan (P=0.001, vs. vehicle), and 31 days with levosimendan plus valsartan (P<0.001, vs. vehicle). The respective survivals were 0%, 16%, 20% and 59%, and the respective incidences of severe lesions were 50%, 67%, 50% and 11%. In this rat model, levosimendan increased blood volume of the cerebral vessels, with significant effects in the microvessels of the cortex (∆R=3.5±0.15 vs. 2.7±0.17ml for vehicle; P=0.001) and hemisphere (∆R=3.2±0.23 vs. 2.6±0.14ml for vehicle; P=0.018). Overall, levosimendan significantly reduced stroke-induced mortality and morbidity, both alone and with valsartan, with apparent cumulative effects, an activity in which the vasodilatory effects of levosimendan have a role.

KEYWORDS:

Animal model; Cerebral blood volume; Hypertension; Levosimendan; Stroke; Survival

PMID:
25641751
DOI:
10.1016/j.ejphar.2015.01.037
[Indexed for MEDLINE]
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